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To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium\/calmodulin\u2010dependent protein kinase kinase 2 (CAMKK2)\u2010mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum\u2010chloride\u2010D\u2010galactose (AlCl3\u2010D\u2010gal)\u2010induced AD rat model. Rats were distributed into four groups: control, AlCl<jats:sub>3<\/jats:sub>\u2009+\u2009D\u2010gal (10\u2009+\u200960\u2009mg\/kg, ip), Vit.D (500\u2009IU\/kg, po), and AlCl<jats:sub>3<\/jats:sub>\u2009+\u2009D\u2010gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (<jats:italic>VDR<\/jats:italic>) and <jats:italic>peroxisome\u2010proliferator\u2010activated\u2010receptor\u2010\u03b3\u2010coactivator\u20101\u03b1<\/jats:italic> <jats:bold>(<\/jats:bold><jats:italic>PGC\u20101\u03b1<\/jats:italic>) expression by quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR), CAMKK2, p\u2010SIRT1, phosphorylated\u2010AMP\u2010activated protein kinase (p\u2010AMPK), dynamin\u2010related\u2010protein\u20101 (Drp1), and mitofusin\u20101 (Mnf1) proteins by western blot and Ca<jats:sup>2+<\/jats:sup> levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (A\u03b2), and phospho tau (p\u2010Tau) via enzyme\u2010linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D\u2010attenuated hippocampal injury reversed the cognitive decline and A\u03b2 aggregation, and elevated p\u2010Tau levels in the AlCl<jats:sub>3<\/jats:sub>\u2009+\u2009D\u2010gal\u2010induced AD rat model. In AlCl<jats:sub>3<\/jats:sub>\u2009+\u2009D\u2010gal\u2010exposed rats, Vit.D induced <jats:italic>VDR<\/jats:italic> expression, normalized Ca<jats:sup>2+<\/jats:sup> levels, elevated CAMKK2, p\u2010AMPK, p\u2010SIRT1, and <jats:italic>PGC\u20101\u03b1<\/jats:italic> expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl<jats:sub>3<\/jats:sub>\u2009+\u2009D\u2010gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3\u2009+\u2009D\u2010gal\u2010induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2\u2010AMPK\/SIRT1 pathway upregulation.<\/jats:p>","DOI":"10.1002\/biof.2013","type":"journal-article","created":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T05:11:34Z","timestamp":1696655494000},"page":"371-391","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Neuroprotective effects of vitamin <scp>D<\/scp> in an <scp>Alzheimer's<\/scp> disease rat model: Improvement of mitochondrial dysfunction via calcium\/calmodulin\u2010dependent protein kinase kinase 2 activation of <scp>Sirtuin1<\/scp> phosphorylation"],"prefix":"10.1002","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3827-9647","authenticated-orcid":false,"given":"Marwa","family":"Mohanad","sequence":"first","affiliation":[{"name":"Department of Biochemistry, College of Pharmaceutical Sciences and Drug Manufacturing Misr University for Science and Technology (MUST)  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimaa K.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Helwan University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basma E.","family":"Aboulhoda","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Faculty of Medicine Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha A. 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